This is a multidisciplinary investigation of normal aging in the rhesus monkey. The goal is to discover the cascade of events that constitute the pathogenic mechanisms of normal aging in the primate cerebral cortex. Our investigations show that cognitive impairments appear by 20 years of age but range from mild to severe. Thus, some animals are severely impaired while others ~successfully~ age. Surprisingly, we find that cortical neurons are not lost and synapse numbers in cortex appear to be preserved. In contrast, some subcortical neurons that project to cortex are lost, volumetric MRI studies demonstrate age-related reduction in white matter and EM studies reveal degenerative changes in myelin. In addition, oxidative metabolism is reduced, specific neurotransmitter receptors are altered and layer I shows frank degeneration. These observations lead to our hypothesis that cortical dysfunction causes age-related cognitive impairments. We will test this hypothesis and examine underlying mechanisms by comparing young monkeys (aged 5 to 10) and monkeys (20 and over). All subjects will be tested on behavioral tasks assessing memory and executive system function and receive MRI and PET scans. Callosal evoked responses and PET activation will also be studied. Subjects will be divided into three perfusion groups matched on the basis of age and cognitive impairment. In this way, all groups will have both impaired and ~successfully~ aged subjects. One group will be perfused with mixed aldehydes and their brains examined by light and electron microscopy to identify age-related changes in cortical neurons, myelin and glial cells, the neuropil of layer I and subcortical neurons that project to cortex. The second group will be perfused with 4% paraformaldehyde to provide material for immunocytochemical studies of neurons, myelin, glia, layer I and neurons. The third group will be perfused with Krebs buffer to provide fresh and fresh frozen material. Fresh tissue blocks will be used for in vitro slice neurophysiology and in vitro slice biochemistry and frozen blocks will be used for biochemical and molecular experiments. Cryostat sections will be used for ligand binding, in situ hybridization and immunocytochemical studies of neurotransmitter receptor systems and oxidative metabolism. The biochemical and molecular studies will assess the role of nitric oxide synthase and immune system proteins as pathogenic mechanisms underlying the age-related cortical dysfunction. The results of our assessment of the changes in the brain that underlie age-related cognitive impairments will provide a basis for future tests of therapeutic intervention in this model of normal human aging.